ABSTRACT Opioid use during pregnancy is a national epidemic. Prenatal opioid exposure occurs at a time of rapid fetal brain development, and may cause important long-term structural and functional neurologic problems in the exposed child. However, children with prenatal opioid exposure are also often exposed to maternal mental health problems, poor parenting, and adverse home environments. It is critical to determine the relative impacts of multiple adverse exposures on childhood outcomes and identify potentially modifiable factors. The goal of the Outcomes of Babies with Opioid Exposure (OBOE) study is to characterize the multidimensional impact of prenatal opioid exposure and to identify modifiable risk factors for adverse sequelae in order to optimize neurodevelopmental, behavioral, and family outcomes. Specific aims are: (1) To determine the impact of prenatal opioid exposure on brain structure and connectivity over the first 2 years of life, (2) To define medical, developmental, and behavioral outcomes over the first 2 years of life in infants exposed to opioids, and (3) To explore whether and how the home environment, maternal mental health, and parenting modify trajectories of brain connectivity and neurodevelopment over the first 2 years of life. We hypothesize that neural connectivity and neuroanatomical volumes are altered by prenatal opioid exposure and that the magnitude of these alterations correlate with developmental and behavioral outcomes. Further, family and environmental factors interact with prenatal opioid exposure to influence the trajectories of connectivity, development, and behavior over the first 2 years of life. To test this hypothesis, our consortium will enroll 200 opioid exposed infants and 75 healthy appropriately matched controls in a multicenter longitudinal cohort study. We will assess brain volumes and structural and functional connectivity by MRI at 2 weeks, 6 months, and 24 months and behavior and development at 12 and 24 months. The home environment will be assessed with a standardized tool at 12 months. Our consortium consists of a Data Coordinating Center at RTI and four Clinical Sites, all of whom have extensive experience collaborating in multicenter longitudinal pediatric research. Study team members have significant expertise in longitudinal neonatal follow-up, epidemiology, clinical trials, health disparities, neuroimaging, and NOWS. The Clinical Site at CHOP/PENN brings essential expertise in longitudinal follow-up of high-risk populations, advanced statistical methods such as causal inference, serial neuroimaging in infants and toddlers, and exceptional track records of recruitment and retention in neonatal clinical research to the OBOE consortium, ensuring success of this important study.